PROJECT SUMMARY: With the widespread use of combination antiretroviral agents, the incidence of HIV-associated nephropathy (HIVAN) has dramatically decreased in the recent years. Yet, the prevalence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in HIV sero-positive patients remains high, suggesting that HIV-positive patients are at increased risk for a variety of acute and chronic kidney diseases. Indeed, several lines of evidence from recent epidemiological and animal model studies indicate that concurrent HIV infection and age-related comorbidities, such as diabetes mellitus, have a synergistic effect on the incidence of chronic kidney disease, thereby necessitating an examination of mechanisms by which HIV infection accelerates the progression of CKD such as diabetic kidney disease (DKD). We have recently shown that the upregulation of local inflammation induced by HIV aggravates the progression of DKD through increased transcriptional activities of NF- ?B and STAT3, indicating that HIV-induced chronic inflammation may predispose and excerbate the course of non-HIV related CKD. We have also shown that SIRT1 histone deacetylase is a key modulator of the transcriptional activities of NF-?B and STAT3 in diabetic kidneys, suggesting that pro-inflammatory responses that drive CKD progression may share a common pathway. We therefore posit that SIRT1 is a central modulator of chronic HIV infection-induced inflammation through deacetylation of key transcription factors such as NF-?B and STAT3, and that the regulation of SIRT1 and NF-?B may be effective therapeutic approaches against HIV-induced CKD. Using small molecule agonist of SIRT1 and antagonist of NF-?B, and novel transgenic mouse models, we propose to determine the role of SIRT1 in regulating HIV-mediated cellular injuries in diabetic kidneys. Our results will provide a better understanding of the underlying molecular mechanisms by which chronic HIV infection accelerates the progression of CKD and a proof-of-concept for novel target treatment for CKD in HIV patients.